This invention relates to rapamycin derivatives, pharmaceutical compositions comprising such derivatives, methods of treatment of disease states caused by pathogenic fungi, and methods of inducing desirable immunosuppression utilizing such rapamycin derivatives.
Rapamycin is a naturally occurring macrocyclic triene antibiotic which can be produced by culture techniques. Its structure may be illustrated as follows: ##STR1##
At least one rapamycin-producing strain of Streptomyces hygroscopius has been deposited with the Northern Utilization and Research Division, Agricultural Research Service, U.S. Department of Agriculture, Peoria, Ill., U.S.A. under accession number NRRL 5491. Rapamycin, and methods for its preparation by culturing NRRL 5491 are disclosed in U.S. Pat. No. 3,929,992, issued Dec. 30, 1975, the entire disclosure of which is hereby incorporated by reference.
There exist a variety of disease states in humans and other animals the treatment or prevention of which is benefitted by a therapeutic induction of immunosuppression. Such disease states include a whole host of inflammatory and autoimmune diseases and also include resistance to or rejection of transplanted organs.
Cyclosporine is widely used therapeutically when immunosuppression is desired, especially for the prevention of rejection of transplanted organs. However, cyclosporine is known to be nephrotoxic. Similarly, corticosteroids have long been used for immunosuppression, especially in the treatment of disease state caused by inflammation. However, corticosteroids are generally considered to exhibit a high systemic toxicity.
Amphotericins are used for the treatment of fungal infections. However, these compounds are nephrotoxic and lack a desirably broad spectrum of antifungal activity.
Thus, it may be appreciated that immunosuppressants and antifungal compounds having a more attenuated toxicity profile than the presently known therapeutic compounds are desirable.